Accreditation Statement

This activity has been designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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NCCN designates this educational activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-16-008-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/79274; and 4) view/print certificate.

Release date: August 10, 2016; Expiration date: August 10, 2017

Learning Objectives:

Upon completion of this activity, participants will be able to:

• Integrate into professional practice the updates to NCCN Guidelines for Melanoma

• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Melanoma

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NCCN Guidelines Insights: Melanoma, Version 3.2016

Version 3.2016 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 8; 10.6004/jnccn.2016.0101

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Checkpoint Immunotherapy

Some of the most effective immunotherapies target immune checkpoints exploited by cancers to decrease immune activity. For example, activation of T-helper cells upon binding to antigens on the antigen-presenting cell (APC) can be modulated by other receptor-ligand interactions between the 2 cells. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are 2 examples of receptors on T cells that, upon ligand binding, trigger a signaling cascade that inhibits T-cell activation, limiting the immune response.^15–18 Antibodies against these receptors (ipilimumab, nivolumab, pembrolizumab) prevent receptor-ligand interaction, removing the inhibition of T-cell activation and “releasing the brake” on the immune response.^19–21

Pembrolizumab: Randomized trials in patients with unresectable stage III or IV metastatic disease have shown that pembrolizumab (monotherapy), like nivolumab, improves response and progression-free survival (PFS) compared with chemotherapy or ipilimumab (monotherapy), and is associated with lower risk of adverse events (Table 1).¹² Results from KEYNOTE-006 showed that pembrolizumab also improved overall survival (OS) compared with ipilimumab.¹² The efficacy and safety of pembrolizumab did not appear to be significantly affected by the dose level (2 mg/kg vs 10 mg/kg) and frequency (every 2 weeks [Q2W] or every 3 weeks [Q3W]), and all the regimens tested in these trials improved response and outcomes compared with controls.^7,12,22

Nivolumab: Two phase III clinical trials have demonstrated nivolumab efficacy in previously untreated unresectable stage III or IV melanoma (Table 2). Results from CheckMate 066 showed that nivolumab improved response rate, PFS, and OS compared with chemotherapy.⁸ The percent grade 3/4 adverse events was lower with nivolumab compared with chemotherapy.⁸ Remarkably, the survival curve suggests that nivolumab may lead to long-term survival in at least 50% of patients. Results from CheckMate 067 showed that nivolumab (monotherapy) improved response rate and PFS compared with single-agent ipilimumab, and was associated with lower toxicity.⁴

The results of CheckMate 066 and 067 demonstrated that, in the first-line setting, nivolumab is a better option than chemotherapy or ipilimumab for patients with unresectable or metastatic disease.^4,8 An ongoing trial, CheckMate 037, has shown that nivolumab also improves response rate compared with chemotherapy in patients with previously treated unresectable stage III or IV melanoma (Table 2).¹ Safety results suggest that nivolumab may be better tolerated than chemotherapy in heavily pretreated patients with advanced disease.¹ Further follow-up is needed to verify whether nivolumab improves PFS or OS in patients with previously treated advanced disease.

Anti–CTLA-4/Anti–PD-1 Combination Therapy: As shown in Table 2, results from 2 randomized trials demonstrated that ipilimumab/nivolumab combination therapy significantly improved response and PFS compared with ipilimumab monotherapy in patients with previously untreated unresectable stage III or IV disease.^4,11 Further follow-up is needed to determine whether nivolumab/ipilimumab combination therapy improves OS compared with single-agent ipilimumab. Both these trials also showed substantially increased toxicity with immune checkpoint combination therapy versus monotherapy.

Anti–PD-1 Therapy in Patient Subpopulations: BRAF Mutation Status: Subgroup analyses in the CheckMate and KEYNOTE trials showed that both patients with BRAF-mutant tumors and those with BRAF wild-type tumors derived clinical benefit from anti–PD-1 therapy compared with controls (single-agent ipilimumab or chemotherapy).^1,4,7,12 Likewise, subgroup analyses in CheckMate 067 and 069 showed improved efficacy with nivolumab/ipilimumab combination therapy compared with ipilimumab monotherapy regardless of BRAF mutation status.^4,11

Table 1.

Pembrolizumab Trials in Advanced Melanoma^a

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PD-L1 Expression: To determine whether the PD-1 ligand (PD-L1) could be used to identify candidates for anti–PD-1 therapy, PD-L1 expression was assessed in tumor samples from patients in the CheckMate and KEYNOTE trials, and expression level cutoffs were chosen to divide patients into “PD-L1–positive” and “PD-L1–negative” subgroups.^1,4,8,11,23 Across trials, results showed that for both subgroups, anti–PD-1 monotherapy provided clinical benefit compared with controls (single-agent ipilimumab or chemotherapy), and nivolumab/ipilimumab combination therapy improved efficacy compared with ipilimumab. The apparent prognostic value of PD-L1 may have been limited by the expression assays and cutoffs used in these studies. Although PD-L1 expression assays continue to be developed, they are not in current form sufficiently reproducible, widely available, nor discriminative for screening patients with melanoma.

Brain Metastases: In the CheckMate and KEYNOTE trials, 3% to 19% of patients had brain metastases (Tables 1 and 2). Ongoing trials have been designed to specifically address the safety and efficacy of anti–PD-1 in patients with melanoma brain metastases (ClinicalTrials.gov identifiers: NCT02320058, NCT02374242, and NCT02621515).

Before or After Anti–CTLA-4 Therapy: Ongoing studies are aimed at determining the efficacy of sequential monotherapy with ipilimumab and PD-1 inhibitor. Preliminary results from a randomized phase II trial show similar safety but improved response for patients treated with nivolumab followed by ipilimumab compared with patients who received these therapies in the reverse order.²⁴

Checkpoint Immunotherapy Treatment Administration: The ipilimumab treatment regimen of 3 mg/kg Q3W for 4 doses is well supported by clinical trial data and approved by the FDA.^25–27 For anti–PD-1 agents, however, there are fewer data to support the optimal dose and duration of treatment. Tables 3, 4 and 5 summarize the treatment dosing and duration

Table 2.

Nivolumab Trials in Advanced Melanoma^a

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Although the product labels for nivolumab and pembrolizumab indicate that treatment should continue until disease progression or unacceptable toxicity,^28,29 the published trials allowed shorter or longer treatment in certain situations. Discontinuation is common among patients treated with anti–PD-1 therapy, and hence clinical experience with treatment beyond 1 year is currently limited. For the trials listed in the tables, results published thus far (median follow-up <2 years) show discontinuation rates of 45% to 77% in patients treated with anti–PD-1 therapy. In the KEYNOTE-002 study, pembrolizumab was administered for a maximum of 24 months. Further follow-up should indicate whether anti–PD-1 treatment beyond 2 years is needed to maintain disease control. Studies are needed to explore this question and test whether switching to lower-frequency maintenance therapy is sufficient to maintain long-term clinical benefit.

BRAF-Targeted Therapies

Approximately half of patients with metastatic cutaneous melanoma harbor an activating mutation of BRAF, an intracellular signaling kinase in the

Table 3.

Nivolumab Treatment Regimens

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BRAF Inhibitor Monotherapy: Vemurafenib and dabrafenib were developed to inhibit BRAF with mutations at V600.^34–36 For patients with previously untreated stage IV or unresectable stage III melanoma, phase III trials (BRIM-3, BREAK-3) have shown that monotherapy with either of these agents improves response rates, PFS, and OS compared with chemotherapy (dacarbazine; Tables 6, 7 and 8). For both vemurafenib (Table 6) and dabrafenib (Table 7), efficacy in patients with previously treated advanced disease, including those who received prior ipilimumab, is supported by single-arm open-label trials (ClinicalTrials.gov identifier: NCT00949702; BREAK-2) showing response rates, median PFS, and median OS similar to those from the phase III trials (BRIM-3, BREAK-3). Phase III trial results show that time to response for BRAF inhibitors (median ≈1.5 months) was shorter than with chemotherapy (Table 7), and when compared with data from other trials, seems to be shorter than for checkpoint immunotherapy (median, 2.1–3.5 months; Tables 1, 2, 6, 7 and 8). Responses to BRAF inhibitor monotherapy were relatively short-lived, however, with median duration of approximately 5 to 7 months (Tables 6 and 7). Likewise, PFS and OS Kaplan-Meier curves for vemurafenib and dabrafenib show little or no decline during the first few months of treatment (≈1.5 months for PFS, ≈3 months for OS), and then abruptly begin to decline.^13,37 Both dabrafenib and vemurafenib have been tested in noncomparative trials (ClinicalTrials.gov identifier: NCT01307397; BREAK-MB) as single-agent therapy in patients with asymptomatic brain metastases (Table 6 and 7). Response rates for vemurafenib (24%)⁶ and dabrafenib (31%–38%; Table 7) were lower than for patients without brain metastases, but are nonetheless notable in the context of this difficult-to-treat population.

BRAF/MEK Inhibitor Combination Therapy: Despite high initial response rates, half of the patients treated with BRAF-targeted monotherapies relapse within around 6 months, due to development of drug resistance.^37–39 Alternate methods for targeting the MAP kinase pathway are being explored as options for overcoming resistance to BRAF inhibitor therapy. Trametinib and cobimetinib are oral small-molecule inhibitors of MEK1 and MEK2, signaling molecules

Table 4.

Pembrolizumab Treatment Regimens

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Table 5.

Ipilimumab/Nivolumab Combination Treatment Regimens

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Although MEK inhibitor monotherapy has limited utility for treating advanced metastatic melanoma, phase III trials have now demonstrated that combination therapy with a BRAF and MEK inhibitor has better efficacy than BRAF inhibitor monotherapy for previously untreated unresectable or metastatic disease (Table 8).^2,9,14 When compared with either single-agent dabrafenib or single-agent vemurafenib, combination therapy with dabrafenib and trametinib improved response rate, duration of response, PFS, and OS.^2,9 Likewise, combination therapy with vemurafenib and cobimetinib improved response and PFS compared with single-agent vemurafenib.¹⁴ Further follow-up is needed to determine whether vemurafenib/cobimetinib also improves OS.

Little clinical data are available regarding the efficacy of BRAF/MEK combination therapy in patients with previously treated advanced melanoma. Results from phase I/II studies (Table 8) showed that in patients whose disease had progressed on previous BRAF inhibitor treatment, dabrafenib/trametinib combination therapy was associated with a relatively

Table 6.

Vemurafenib Monotherapy in Advanced Melanoma^a: Key Trials

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Table 7.

Dabrafenib Monotherapy in Advanced Melanoma^a: Key Trials

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First-Line Systemic Therapy

For first-line therapy of unresectable or metastatic disease, recommended treatment options include checkpoint immunotherapy, BRAF-targeted therapy for patients with BRAF-mutated disease, or clinical trial (see ME-E, page 947).

Checkpoint immunotherapy options in this setting include anti–PD-1 monotherapy with pembrolizumab (category 2A), nivolumab (category 1), or nivolumab/ipilimumab combination therapy (category 2A). Checkpoint inhibitors have been shown to be effective regardless of BRAF mutation status. The NCCN Melanoma Panel considers all recommended checkpoint immunotherapy options appropriate for both BRAF mutant and BRAF wild-type metastatic disease. There is interest in PD-L1 as a predictive biomarker for response to anti–PD-1 therapy, but to date it has not been discriminant enough to be used to inform treatment decisions in clinical practice.

Although ipilimumab is FDA-approved for the treatment of unresectable or metastatic melanoma, including both treatment-naïve and previously treated disease, single-agent ipilimumab monotherapy is no longer an NCCN-recommended first-line therapy option due to results from the CheckMate 067 phase III trial showing improved outcomes with anti–PD-1 monotherapy or nivolumab/ipilimumab combination therapy compared with ipilimumab monotherapy.

Selection between anti–PD-1 monotherapy and nivolumab/ipilimumab combination therapy should be informed by the consideration that although combination therapy has been shown to provide somewhat better PFS, it is associated with a much higher risk of serious immune-mediated toxicities, and there is currently no evidence of improvement in OS. Treatment selection should therefore be informed by consideration of the patient's overall health, medical history, concomitant therapies, comorbidities, and compliance with proactive monitoring and management of adverse events.

For patients with BRAF-mutant metastatic disease, BRAF-targeted first-line therapy options include BRAF/MEK inhibitor combination therapy

Table 8.

BRAF/MEK Inhibitor Combination in Advanced Melanoma^a: Key Trials

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Table 9.

NCCN Recommended Dosing Regimens

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For patients with documented BRAF V600 mutations, selection between first-line checkpoint immunotherapy and BRAF-targeted therapy can be difficult given the lack of comparative phase III clinical trials. Clinical trials are underway to address unanswered questions regarding the optimal sequencing and/or combination of these agents. The recommendation for first-line systemic therapy should be informed by the tempo of disease and the presence or absence of cancer-related symptoms. Given that responses to checkpoint immunotherapy can take longer to develop, BRAF-targeted therapy may be preferred in cases in which the disease is symptomatic or rapidly progressing or the overall health of the patient appears to be deteriorating. Patients with low-volume, asymptomatic metastatic melanoma may be good candidates for checkpoint immunotherapy, because there may be time for a durable antitumor immune response to emerge. Safety profiles and approaches to adverse event management differ significantly for BRAF-targeted therapy versus checkpoint immunotherapy; treatment selection should therefore be informed by consideration of the patient's overall health, medical history, concomitant therapies, comorbidities, and compliance.

Second-Line or Subsequent Systemic Therapy

For patients whose disease progresses on first-line therapy or who achieve maximum clinical benefit from BRAF-targeted therapy (if BRAF-mutated), options for second-line therapy depend on ECOG performance status (PS). Patients with poor performance (PS 3–4) should be offered best supportive care. Patients with PS 0–2 have a variety of options depending on their BRAF status and treatment history. Based on the positive results from phase III trials supporting the recommended first-line therapies, the following checkpoint immunotherapy and BRAF-targeted therapy regimens have been incorporated into the guidelines in the setting of second-line or subsequent therapy for qualifying patients: nivolumab, pembrolizumab, nivolumab/ipilimumab combination, dabrafenib, vemurafenib, dabrafenib/trametinib or vemurafenib/cobimetinib combination. Because of the lack of phase III trial data in patients with previously treated metastatic disease, however, these regimens are category 2A (rather than category 1) recommended options for second-line or subsequent systemic therapy. As described in previous sections, results from phase II or IV trials in patients with previously treated advanced disease support use in second-line or subsequent systemic therapy for some of these options (eg, vemurafenib, dabrafenib, pembrolizumab).

In addition to the checkpoint immunotherapy regimens recommended for first-line, second-line, and subsequent treatment of metastatic disease, single-agent ipilimumab is an option in patients who have received prior systemic therapy for metastatic disease. This recommendation is based on the results from the pivotal phase III trial (CA184-002) in patients with previously treated unresectable stage III or IV melanoma.

Of the recommended options for second-line and subsequent therapy, the NCCN Melanoma Panel recommends considering only those agents that are not the same or of the same class as the agents the patient received previously. Patients treated with ipilimumab who experience stable disease of 3 months' duration after week 12 of induction or partial or complete response, who subsequently experience progression of melanoma, may be offered reinduction with up to 4 doses of ipilimumab at 3 mg/kg Q3W. Although anti–CTLA-4 (ipilimumab) and anti–PD-1 (nivolumab, pembrolizumab) agents are both checkpoint immunotherapies, they are not considered the same class of agent because they target different molecules. For patients who previously received ipilimumab, subsequent treatment with anti–PD-1 therapy is a recommended option, and vice versa. Patients whose disease previously progressed or who achieved maximal response on BRAF inhibitor therapy are unlikely to benefit from BRAF/MEK combination therapy. Likewise, patients whose disease progressed or achieved maximal response on BRAF/MEK combination therapy are unlikely to respond to BRAF monotherapy or a different BRAF/MEK combination. For patients who have progressed on checkpoint immunotherapies (and BRAF-targeted therapy if BRAF-mutated), additional options to consider for second-line or subsequent therapy include high-dose interleukin-2, biochemotherapy (category 2B), cytotoxic agents, and imatinib for tumors with activating mutations of C-KIT. It is not known which of these options may provide benefit, because data supporting these approaches largely predate the development checkpoint inhibitor and BRAF-targeted therapies.

Immune Checkpoint Inhibitor Administration

Ipilimumab is FDA-approved for the treatment of unresectable or metastatic melanoma at a dose of 3 mg/kg of body weight, administered Q3W for a total of 4 doses, consistent with the dosing regimen in the phase III trials described.²⁷ The NCCN Melanoma Panel recommend the use of ipilimumab at the FDA-approved dose and schedule.

As described earlier, FDA-recommended dosing regimens indicate that treatment should continue until disease progression or unacceptable toxicity for all 3 of the approved regimens containing anti–PD-1 agents: nivolumab, pembrolizumab, and nivolumab/ipilimumab combination therapy. Due to the lack of data on long-term anti–PD-1 treatment, the optimal treatment duration is unknown. In the absence of unacceptable toxicity, it is common practice to continue anti–PD-1 therapy until maximal response. Although there is no standard definition for maximal response, it is commonly defined as no additional tumor regression on at least 2 consecutive scans taken at least 12 weeks apart. Treatment after maximal response is controversial. Continuing anti–PD-1 treatment for one 12-week cycle after maximal response has been achieved is not uncommon in clinical practice. NCCN-recommended dosing regimens are listed in Table 9.